Anil Kumar Mantha

Synaptic failure is one of the earliest and most significant contributors to the cognitive decline in Alzheimer’s disease (AD), preceding extensive neuronal loss. Although amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein characterize the disease, memory impairment primarily results from the gradual deterioration of synaptic communications. This decline is caused by a complex interaction among mitochondrial energy deficits, cytoskeletal instability, disrupted exosomal signaling, and immune-mediated synaptic pruning. Mitochondrial dysfunction, particularly affecting complexes I and IV, leads to reduced ATP production, faulty mitophagy and disrupted calcium (Ca ²⁺ ) homeostasis, placing the synapse under constant metabolic stress. Elevated reactive oxygen species (ROS) further activate stress pathways, including p38 MAPK and JNK, contributing to synaptic protein damage and impaired long-term potentiation (LTP). Furthermore, tau hyperphosphorylation destabilizes the neuronal cytoskeleton, weakening dendritic spine integrity and synaptic connectivity. At the same time, Aβ alters the cargo carried by exosomes, facilitating the spread of pathogenic Aβ and tau species between the neurons and modulating microglial activation and complement-mediated synaptic pruning. Additionally, emerging studies highlight the role of NETosis in exacerbating neuroinflammation and compromising the blood-brain barrier (BBB) integrity, thereby increasing synaptic damage. In contrast, phytochemicals such as resveratrol, ginkgolide B, curcumin, ferulic acid, epigallocatechin gallate (EGCG), and quercetin exert neuroprotection by restoring redox balance, altering exosomal communications, stabilizing cytoskeletal signaling, and reducing neuroinflammation. Moreover, delivery techniques such as nanoparticles and engineered exosomes enhance BBB permeability and enable targeted synaptic intervention. Overall, this review summarizes current mechanistic findings and highlights the potential of phytochemicals as multitarget therapeutic agents for synaptic repair and functional recovery in AD.

Alzheimer’s disease (AD) is a common neurodegenerative disease of the elderly and the sixth leading cause of death. Various risk factors are responsible for the disease, including aging, vascular disorders, head trauma, infection, genetics, and environmental conditions. Amyloid beta (Aβ) and neurofibrillary tangle (NFT) build-up lead to the generation of free radicals, which in turn cause oxidative stress and neuroinflammation that further cause synaptic and mitochondrial dysfunction. These inflammatory responses primarily stem from the overactivation of microglial and astroglial cells, producing cytokines and chemokines. However, immune cell migration has also been observed in the central nervous system (CNS) via blood–brain barrier (BBB) disruption, in which neutrophils have grabbed more attention due to their migration and formation of neutrophil extracellular traps (NETs) in AD brain parenchyma and blood vessels, causing chronic neuroinflammation and neuronal damage via NETosis. NETosis is the immune system’s defense mechanism in which neutrophils form web-like structures to trap pathogens and digest them with their antimicrobial and cytotoxic peptides and release inflammatory cytokines. Neutrophils and NETs have been observed in many studies surrounding Aβ plaques in the brain parenchyma and cerebral blood vessels, causing neuronal tissue damage and AD progression. The ongoing research advocates that by targeting conventional Aβ plaques and tau build-up, managing neuroinflammation, particularly caused by NETosis, may delay the onset or reduce its progression. In the growing health care scenario, to avoid any side effects and the cost of the present discovered drugs, the focus should be on organic or natural components/compounds for which phytochemicals will be the best to target NETosis, as they have many medicinal properties like anti-oxidant, anti-inflammatory, anti-microbial, and immunomodulatory. This review focuses on understanding the molecular association between neuroinflammation in NETs and AD progression and the role of plant-derived constituents in tackling the NETosis-induced AD progression.

The Apurinic/Apyrimidinic endonuclease 1 (APE1/Ref-1) is essential for controlling the oxidative DNA base damage via the Base Excision Repair (BER) pathway. While APE1’s N-terminal region is important in redox function (named redox effector factor 1, Ref-1) and protein-protein interactions, its C-terminal region is involved in DNA repair activities. In this work, we employed the Aβ_25–35 peptide to produce oxidative stress in order to assess the protective effects of two phytochemicals, ferulic acid (FA) and Ginkgolide B (GB), individually and in combination, with a focus on APE1 in different subcellular compartments of human neuroblastoma SH-SY5Y cells. Exposure to Aβ_25–35 reduced the APE1 levels in the mitochondrial, nuclear, whole-cell, and exosomal extracts, resulting in oxidative DNA base damage, which resulted in the accumulation of DNA base lesions, further compromising neuronal homeostasis. Moreover, Aβ_25–35 suppressed the activation of important transcription factors, including Nrf-2 and CREB, necessary for neuroprotection, synaptic plasticity, and antioxidant defense, by inhibiting APE1’s redox activity. Neurodegenerative processes and elevated oxidative stress were exacerbated by the absence of these defensive mechanisms. On the other hand, pre-treatment with the phytochemicals FA and GB, both individually and synergistically, successfully restored APE1 expression and functionality in different subcellular compartments. In addition to improving BER efficiency by lowering oxidative DNA damage, this also restored APE1’s redox activity, which made it easier for Nrf-2 and CREB to activate. By modifying APE1-dependent repair and redox pathways, these factors reduced Aβ-induced oxidative stress and neuronal damage, indicating their potential as therapeutic agents in Alzheimer’s disease (AD).

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by memory loss, synaptic impairment, and biochemical changes. The study aimed to investigate the neuroprotective role of ferulic acid (FA) in an AD mouse C57BL/6 model induced by the Aβ(25-35) peptide. Cognitive deficits, which include memory and spatial learning deficits caused by Aβ, were evaluated using a set of behavioural tests. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and Western blot analysis were used to characterize the exosomes from the brain and the serum. The activity of acetylcholinesterase (AChE) in exosomes was also evaluated, and the proteomic analysis of the serum-derived exosomes was conducted through LC-MS Triple ToF and bioinformatics to identify the altered pathways associated with identified proteins. The results obtained showed that there were significant alterations in the exosomal proteome profile after Aβ treatment. The levels of some of the proteins that are involved in energy metabolism, amyloid clearance, cytoskeleton, oxidative stress, and neuroinflammation were particularly affected. Treatment with the phytochemical FA modulated the exosomal proteome profile alterations and the activity of AChE in exosomes, which are some of the hallmarks of cholinergic dysfunction in the case of AD. However, the analysis of the proteome of the AD condition revealed that there were distinct alterations in the content of serum-derived exosomes, which could be used as candidates for non-invasive biomarkers of AD progression. This work also highlights the possibility of using the phytochemical FA to prevent and treat the neurotoxicity and neurodegenerative cascade induced by Aβ and to correct the protein content of exosomes in AD.

The central nervous system (CNS) involves a complex interplay of communications between the neurons and various glial cells, which is crucial for brain functions. The major interactomes are exosomes that transmit sundry molecules (DNA, miRNAs, and proteins) between the cells and thus alter cell physiology. Exosomes can act as neuroprotective or neurodegenerative agents depending on the microenvironment of cells secreting them. Therefore, revealing exosome proteome becomes important to understand donor cells' physiology and its effect on the recipient cell. In this study, oxidative stress was induced by Aβ_25-35 in the human neuroblastoma SH-SY5Y cells and the protective effects of phytochemical ferulic acid (FA) were evaluated alone and in combination with Aβ_25-35 (pre-treated for 3 h before Aβ_25-35 exposure) and proteome of their secreted exosomes was analyzed, which was carried out via a high-resolution LC–MS Triple-ToF and further network-based analysis has been carried out using various bioinformatics tools. The proteomic profiling enlightened the multiple roles of exosomes as proteins associated with the various pathways advocate that exosomes can mediate a wide range of effects, from normal physiological processes like synaptic plasticity, neuronal metabolic support, nerve regeneration, DNA repair, axon guidance, and long-term potentiation (LTP) to abnormal pathological processes like inflammatory responses, oxidative stress, apoptosis, and formation of neutrophil extracellular traps (NETs). On comparison, treatment with Aβ_25-35 resulted in a significant modulation of the exosomal proteome, promoting pathways associated with neurodegeneration. Conversely, the phytochemical FA displayed a protective effect by effectively countering Aβ_25-35-induced oxidative stress responses linked with neurodegeneration, as seen in Alzheimer’s disease (AD). Taken together, this study highlights the dual role of exosomes in physiological and pathophysiological neurodegenerative AD, which intricately depend on the particular cellular milieu.